Production of 17alpha-hydroxy-20-keto-16beta-methyl steroid derivatives of the pregnane series



United States Patent 3,115,508 PRODUCTION of 17a-HYDRflXY-20-KETO-16B- METHYL STEROHID DERIVATIVES OF THE PREGNANE SERIES Gordon Haniey Philiipps, Greenford, England, assign'or to Glaxo Laboratories Limited, Greenford, England, a company of Great Britain N0 Drawing. Fiied July 26, 1962, Ser. No. 212,737 Claims priority, application Great Britain Aug. 2, 1961 11 Claims. (Cl. 260-39745) This invention is concerned with improvements in or relating to the preparation of steroid derivatives. More particularly, the invention is concerned with the reduction of 16-methylene steroids to the corresponding 16 8- methyl steroids.

In United States Patent No. 3,040,069, there is described a process for the reduction of 17a-hydroxy-20 keto-16-methylene steroids by hydrogenation in the presence of a platinum hydrogenation catalyst or a Raney nickel catalyst, it having been found that by using such a catalyst a mixture of 16aand 16fl-methyl steroids was obtained in which, however, the 16,8-methyl steroid preponderated. Whilst the 16fi-methyl steroid preponderates in the mixture it is still generally necessary to use a purification step to eliminate the unwanted 16a-methyl steroid. In practice such a step has been found to be difficult to carry out and leads to further loss of yield of the desired compound.

It has now been found that if the hydrogenation of 17aydroxy-ZO-keto-16-methylene steroids, particularly 21-acyloxy-17a-hydroxy-20-keto-16-methylene steroids, is effected in the presence of an iridium catalyst the reaction is more stereospecific in favour of the desired 16;?- methyl steroid as evidenced, for example, by optical rotation data and thin layer chromatography compared with the use of platinum or Raney nickel catalysts. In deed in some cases such a high yield of 16B-methyl steroid may be obtained that the need for any purification step is eliminated for practical purposes. The increased stereospecificity of the process and the possible avoidance of the need to separate any 16u-methyl steroid enables one to obtain increased yields of the desired 165- methyl steroid.

According to the invention, therefore, there is provided a process for the production of 17a-hydroxy-20- keto-l6B-methyl steroids which comprises hydrogenating a 17a-hydroxy-20-keto-16-methylene steroid in the presence of an iridium catalyst.

The improved results which may be obtained using iridium are surprising, particularly in view of the fact that iridium has not been found generally to possess any striking merits as a hydrogenation catalyst.

The conditions under which the hydrogenation should be effected vary as between one solvent and another and one carrier and another. The optimum conditions should, therefore, be determined in a given case by preliminary trial. Generally, hydrogenation in ethanol or ethyl acetate has given superior results to other solvents but other solvents may be used including isopropanol. The use of ethyl acetate in particular enables high concentrations to be obtained. The iridium catalyst may consist of iridium metal (free from any support) or iridium metal deposited upon a suitable support. Barium sulphate was found to be a suitable support for the iridium catalyst but other suitable supports e.g. kieselguhr and calcium carbonate may be used, if desired. It is convenient to use a support which can later be dissolved to facilitate recovery of the iridium which is, of course, expensive. cailly suitable. Charcoal was not found to be a particularly suitable support for the hydrogenation of 21-desoxy For this reason, calcium carbonate is especompounds in that the process when conducted in the presence of this support resulted in D-homoannulation of the steroid.

The iridium catalyst may be prepared in the form of its dioxide, if desired deposited on a support. The iridium dioxide may then be subjected to a prereduction step or may be reduced in situ.

The hydrogenation is conveniently effected at atmospheric pressure and at ambient temperature. However, higher pressures and/ or temperatures may be used if desired.

Where the hydrogenation product contains some 16amethyl steroid, purification may be effected as desired, e.g. by repeated crystallisation.

Although 16/3-methyl steroids can be obtained in high yield by hydrogenating 2l-desoxy-17a-hydroxy-20-keto 16-methylene steroids according to the invention, we have found that even higher yields, i.e. greater stereospecificity, can be obtained by hydrogenating 21-acyloxy- 17a-hydroxy-20-keto-16-methylene steroids using iridium as hydrogenation catalyst according to the invention with consequent advantages as described above.

According to a feature of the invention, therefore, the steroid which is hydrogenated in the presence of an iridium catalyst is a 21 acyloxy 17cc hydroxy 20 keto- Iii-methylene steroid.

For practical purposes it is normally convenient to use ZI-acetoxy compounds as the 21-acyloxy compounds and this feature of the invention will be particularly described with reference to such compounds but is not limited thereto.

21 acetoxy a hydroxy 20 keto 16 methylene steroids may be prepared by bromination of the corresponding 21-desoxy compound followed by acetolysis of the resultant 21-bromide.

By using a 2l-acetoxy compound as starting material rather than a 21-desoxy compound it has been found to be possible to obtain very high yields of the desired 16fl-methyl compound on hydrogenation. In some cases it may even be possible to obtain a theoretical yield.

The process according to the invention is believed to be generally applicable to pregnane steroids of the type specified. Such steroids may contain various other substituents including 3-acyloxy, 3-hydroxy or 3-keto groups; ll-acyloxy, ll-hydroxy, or ll-keto groups; 9,11-dichloro groups; 9(11)-dehydro unsaturation and the hydrogen atom, if any, in the 5-position may have the ocor B-configuration. It will be understood that some of these groups, such as 3-keto, may also be reduced during the hydrogenation. If it is desired to obtain 9a-halogeno- 11 fi-hydroxy compounds ultimately, it is advantageous to use steroids of the general formula:

where R is a hydrogen atom or an acyloxy group. Compounds of general Formula I in which R is a hydrogen atom, may be obtained from hecogenin acetate as is described in United States Patent No. 3,040,069 to Phillipps et a1. Compounds of general Formula I in which R is an acyloxy group may be obtained from compounds in which R is a hydrogen atom by bromination and acylolysis.

Compounds of general Formula I in which R is an acyloxy group are novel and are included within the scope of the invention.

Compounds of the above general formula may be hydrogenated according to the invention without, in general, loss of unsaturation at the 9(11)-positions to yield compounds of the general formula:

CH R

Hydrogenation of 21 Acetoxy 3,8,170: Dihydroxy 16- M ethylene-5 a-Pregn-Q-En-ZO-One Using 5% Iridium n Barium Sulphate as Catalyst and Ethanol as Solvent The catalyst (4.0 g.) was shaken for 25 min. in absolute ethanol (100 ml.) under hydrogen at atmospheric pressure and room temperature. The steroid (50 g.) and absolute ethanol (400 ml.) were then added and the suspension was shaken under hydrogen. The rate of uptake of hydrogen became negligible in 310 min. (total uptake 273 ml.) and the hydrogenation was then stopped. The catalyst was removed by filtration and Washed with ethanol, and thecombined filtrates were evaporated to dryness in vacuo. The crystalline residue was desolvated at 100/0.1 mm. to give 2l-acetoxy-3/3,17a-dihydroxy- 16fl-methyl-5a-pregn-9-en-20-one (4.965 g., 99%), M.P. 189.5-194, [aJ +57.5 (c., 1.79 in CHCI The rotation of the product agreed with that of the pure 16p-methyl-compound [a1 +57.5 (CHCl and difiered from that of the 16a-methyl-isomer [001D +23 (CHCl Also, its infra red spectrum resembled that of the 16fl-methyl-compound and thin-layer chromatography on alumina showed that it contained less than 2% of the 16a-methyl-isomer.

When the steroid (1.80 g.) in ethanol (200 ml.) was similarly hydrogenated using 5% platinum on barium sulphate (100 mg.) as catalyst the product (1.81 g.) had [aJ +55.3 (c., 1.52 in CHCl indicating that it contained 94% of the 16 8-methyl compound. Crystallisation of part (1.70 g.) of the product from ethyl acetate (10 ml.) gave the l6/3-methyl-compound (1.384 g., 81.5%), M.P. 194-198, [1x1 +56.7 (c., 1.80 in CHClg), which from its rotation and from thin-layer chromatography contained 0a. 2% of the 16a-isomer.

The starting material used in this example may be prepared as follows:

3,8,17a-dihydroxy-16-methylene-5u-pregn-9-en 20- one (5.0 g.) in suspension in chloroform 100 ml.) was treated with 9.5 N hydrogen chloride in ethanol (11 ml.)

to give a clear yellow solution. Bromine (1.02 mol.) in chloroform (23.5 ml.) was added dropwise over 25 min. to the stirred solution, when a pale brown solution was formed; during a further 10 min. the solution began to darken rapidly. A saturated aqueous solution of sodium hydrogen carbonate (ca. ml.) was added until the aqueous phase became alkaline, the chloroform layer was washed with water, dried over magnesium sulphate and evaporated to dryness in vacuo to leave the crude bromo-compound as a brown froth (7.51 g.).

The froth (7.46 g.) and potassium acetate (22.0 g.) in acetone (200 ml.) were boiled under reflux with stirring for 2 hours. After being cooled, the mixture was treated with sufficient water to give a clear solution, and most of the acetone was distilled off under reduced pressure. Water (ca. 450 ml.) was added and the yellow solid (5.48 g.) was filtered off, washed with water and dried. The crude acetoxylated product (3.9 g.) was recrystallised twice from acetone to give an acetone solvent which, on desolvation at 110/ 0.1 mm., gave 21-acetoxy- 3,8,17a-dihydroxy-16-methylene-5u-pregn-9 en 2O one (1.902 g.), M.P. 193196. Further crystallisation from ethyl acetate gave the analytical sample as prisms (1.20 g.), M.P. 195.5197.5, [u] -21.3 (c., 1.03 1n CHCl (Found: C, 71.3; H, 8.6. C H O requires C, 71.6; H, 8.5%.)

EXAMPLE 2 Hydrogenation of 21 Acetoxy 3,8,17a Dihydroxy 16- Methylene-5a-Pregn-Q-En-ZO-Olle Using 5% Iridium on Barium Sulphate as Catalyst and Ethyl Acetate as Solvent The catalyst (600 mg.) was shaken for 43 min. in ethyl acetate (10 ml.) under hydrogen at atmospheric pressure and room temperature. The steroid (900 mg.) and ethyl acetate (20 ml.) were then added and the suspension was shaken under hydrogen. The rate of uptake of hydrogen became negligible in 190 min. (total uptake 58 m1.) and isolation as in Example 1 then gave the 16,8-methyl-compound (867 mg.), M.P. 192-1995", [aJ +56.7 (c., 1.71 in CHCI which from its rotation and from thinlayer chromatography contained ca. 2% of the'16ot-methyl-isomer.

When the steroid (900 mg.) in ethyl acetate (30 ml.) was similarly hydrogenated using 5% platinum on barium sulphate (100 mg.) as catalyst the product (892 mg.) had [oc] +53.6 (c., 1.75 in CHClg), indicating that it contained ca. 89% of the 16,8-methyl isomer.

EXAMPLE 3 Hydrogenation of 21-Aeetoxy-3fl,17a-Dihydroxy-16-Methylene-5a-Pregn-9-En-20-One Using 5% Iridium on Barium Sulphate as Catalyst and Ethyl Acetate as Solvent at 40 C.

Hydrogenation of the steriod (900 mg.) as in Example 2 but at 40 C. was complete in min. and gave the lfifi-methyl-compound (869 mg), M.P. 189l94, [a] +56.7 (c., 1.7 in CHCl which from its rotation and from thin-layer chromatography contained ca. 2% of the 16ot-methyl isomer.

EXAMPLE 4 Hydrogenation of 2] -Acetoxy-3B,1 7ot-Dihydr0xy-16-Methylene-5a-Pregn-9-En-20-On6 Using 5% Iridium on Kieselguhr as Catalyst and Ethanol as Solvent Hydrogenation of the steriod (900 mg.) in ethanol (100 ml.) using iridium on kieselguhr (600 mg.) as catalyst was complete in 22.5 hr. at room temperature and gave the lfl-methyl-compound (881 mg), M.P. 184- 188, [0:]D +57.3 (c., 1.76 in CHCl which from its rotation contained less than 1% of the l6u-methyl-compound.

EXAMPLE 5 Hydrogenation of 3B,]7a-Dihydroxy-16-Methylene-5a- Pregn-9-En-20-One Using 5% Iridium on Barium Sulphate as Catalyst and Ethanol as Solvent The steroid (1.0 g.) and pro-reduced catalyst (400 mg.) were shaken under hydrogen for 23.5 hr. in ethanol (100 ml.) to give a product (997 mg), [ot] +353 (c., 1.57 in dioxan), which form its rotation contained ca. 90% of 3 5,17a dihydroxy 16 8-methyl-5a-pregn-9-en-20-one (pure compound, [:11 +39) and ca. of the 16mmethyl isomer (pure compound, [a] +2).

EXAMPLE 6 Hydrogenation of 33,17a-Dihydroxy-16-Methylene-Sa- Pregn-9-En-20-One Using Iridium Dioxide as Catalyst The steriod (1.0 g.) and pre-reduced iridium dioxide (40 mg.) were shaken under hydrogen for 22 hr. in ethanol (100 ml.) to give a product (963 mg), [a] +364 (c., 2.09 in dioxan), which from its rotation contained 93% of the 165-methyl-compound.

When the steroid (1.0 g.) was similarly reduced but with Adams platinum dioxide catalyst (12 mg.) the hydrogenation was complete in 160 min. and gave a product (1.00 g), [oc] +338 (c., 2.28 in dioxan), which from its rotation contained ca. 86% of the 16fl-methyl-compound.

EXAMPLE 7 Hydrogenation of 2l-Acetoxy-3/3'17a-Dihydroxy-16-Methylene-5a-Pregn-9-En-20-One Using 7.5% Iridium on Calcium Carbonate as Catalyst and Ethyl Acetate as Solvent The steroid (120.7 g., 0.3 mole) was suspended in ethyl acetate (4.0 litres) and stirred at 31 to make a solution. Iridium on calcium carbonate catalyst (7.5% nominal; 18.0 g.) was added, washed in with ethyl acetate ml.) and the mixture stirred vigorously at 31 under hydrogen. After 18 hr. the uptake of hydrogen had ceased at 7.5 litres (theory 7.32 litres at atmospheric conditions). After removal of the hydrogen the suspension was filtered and the catalyst washed with ethyl acetate (3 x 100 ml). The cloudy filtrate was clarified by filtration through a kieselguhr pad and Washed through with ethyl acetate. The filtrate was evaporated to dryness under reduced pressure at 85 for mins. The product was slurried with acetone (1.0 litre) under reflux to give acetone solvated product (123.0 g.). A sample was dried at 100 in vacuo for 2.5 hrs., [(11 +56.7 (c., 1.8 in CHCI M.P. 194197.

EXAMPLE 8 Hydrogenation of 1 1,8 21 -Diacetoxy-3fi,1 7oa-Dihydroxy- 16-Methylene-5a-Pregnan-ZO-One Using 7.5% Iridium on Calcium Carbonate as Catalyst and Ethyl Acetate as Solvent To a solution of the steroid (5 g.) in ethyl acetate (175 ml.) was added 7.5% iridium-on-calcium carbonate catalyst (0.75 g.). The air above the reaction mixture was replaced by nitrogen and then by hydrogen and the mixture agitated, under hydrogen, at 20 until the uptake of hydrogen ceased. The catalyst was filtered oil, washed with a little ethyl acetate and the filtrate and washes were combined and concentrated to a slurry.

Light pertoleum (B.P. 100/ 120) (20 ml.) was added and the mixture concentrated until all the ethyl acetate had been displaced. The residual slurry was cooled to room temperature and the 116,21-diacetoxy-3fl,17a-dihydroxy-l6,8-methyl-5a-pregnan-20-one was collected by filtration, washed with a little light petroleum and dried at 60, in vacuo (4.95 g., 98.5%), MP. 213-215", [a] +97.7 (dioxan).

The starting material was prepared from 3,3,11,3-d-iacetoxy-Sa-pregn-16-ene-20-one (cf. Callow and James,

E JCS, 1956, 4739) by the steps of reaction with diazo methane, pyrolysis to form a 16-methyl-16(17)-ene compound, epoxidat ion, rearrangement with acid to a 170c-l1ydroxy-16-methylene-compound, bromination to a 21-bromide and reaction with potassium acetate to the 21-acetate.

EXAMPLE 9 Hydrogenation of 21-Aeetoxy-3BJ7a-Dihydr0xy-16- Methylene-5a-Pregn-9-En-20-One Using 7 /2% Iridium on Calcium Carbonate as Catalyst and Ethyl Acetate as Solvent Hydrogenation of the steroid (900 mg.) in ethyl acetate (30 ml.) using 7 /z% iridium on calcium carbonate mg.) as catalyst was complete in 24 hr. at room temperature and gave the 16,8methyl compound (897 mg), M.P. 195-199", [1x1 57.3; its rotation and thinlayer chromatography indicated that it contained 2% of the 16amethyl-compound.

When the steroid (900 mg.) was similarly hydrogenated using 7 /2% platinum on barium sulphate (400 mg.) as catalyst the product (902 mg.) had [a1 +52.7 (in C-HCl indicating that it contained ca. 86% of the 16,8- methyl isomer.

EXAMPLE l0 Hydrogenation of 21 -A cetoxy-3/i,1 7a-Dihydroxy-l 6- Methylene-5a-Pregn-9-En-20-One Using 5% Iridium on Barium Sulphate as Catalyst and Ethyl Acetate as Solvent at Elevated Pressure Hydrogenation of the steroid (900 mg.) in ethyl acetate (30 m1.) using 5% iridium on barium sulphate (600 mg.) as catalyst at room temperature and at 4.2 atmospheres pressure (falling to 2.5 atmospheres in 22 hr.) gave the 16/3-methyl compound (881 mg), M.P. 190-197", [(11 +56.4; thin-layer chromatography indicated that it contained less than 2% of the 16a-methylcompound.

EXAMPLE v11 Hydrogenation of SB-Acetoxy-J 7a-Hydroxy16-Methyl ene-5a-Pregn-9-En-20-One Using 7 /2% Iridium 0n Calcium Carbonate as Catalyst and Ethanol as Solvent Hydrogenation of the steroid (1.0 g.) in ethanol (90 ml.) using 7 /2 iridium on calcium carbonate (600 mg.) as catalyst was complete in 270 min. and gave a product (998 mg), [ab +30.9 (in diox-an); its rotation indicated that it contained ca. 90% of the 16t3-methyl-compound (pure compound, [111 +34) and ca. 10% of the 16a-methyl-compound (pure compound, [a1 +4).

I claim:

:1. A process for the production of 17a-hydroxy-20- keto-16/3-methyl steroids of the pregnane series which comprises hydrogenating a l7a-hydroxy-20-keto-l6- methylene steroid of the pregnane series in the presence of an iridium catalyst.

2. A process as defined in claim 1 in which the iridium is unsupported.

3. A process as defined in claim 1 in which the iridium is supported on a material selected from the group consisting of barium sulphate, k ieselguhr and calcium carbonate.

4. A process as defined in claim 1 in which the iridium is formed by reduction in situ of iridium dioxide.

5. A process as defined in claim 1 in which the chydroxy-20-keto-16-methylene steroid is dissolved in a solvent selected from the group consisting of ethanol and ethyl acetate.

6. A process as defined in claim 1 in which the 170:- hydroxy-20-ketone-l6-methylene steroid is a 21-desoxy steroid.

7. A process as defined in claim 1 in which the 17ahydroxy-ZO-ketone-16-methylene steroid is a 2l-acyloxy steroid.

7 8 8. A process as defined in claim '7 in which the 21- 10. A compound of the formula: acyloxy steroid is a 2l-acetoxy steroid.

9. A process as defined in claim 1 in which the 17* hydroXy-20-keto-16-methylene steroid used has the fr 00 mula:

where R is an a'cyloxy group derived from a lower carboxylic acid.

1 15 11. 21 vacetoxy 3,8,17u dihydroxy 16 methylene H 5o -pregn-9-en-20-one.

Where R is selected from the group consisting of hydrogen and acyloxy groups. No references cited. 

1. A PROCESS FOR THE PRODUCTION OF 17A-HYDROXY-20KETO-16B-METHYL STEROIDS OF THE PREGNANE SERIES WHICH COMPRISES HYDROGENATING A 17A-HYDROXY - 20 - KETO-16METHYLENE STEROID OF THE PREGNANE SERIES IN THE PRESENCE OF AN IRIDIUM CATALSYT.
 10. A COMPOUND OF THE FORMULA: 